High Throughput Screening of Medicines for Malaria Ventures Chemical Libraries to Identify Novel Inhibitors of Candida auris

念珠菌是机会性真菌侵袭的最常见病原体 不断扩大的免疫和药物受损患者的感染范围，以及现在的念珠菌病 是世界上第三到第四最常见的医院感染，其感染率高得令人无法接受 死亡率为30%-60%，令人担忧的是，在过去30年中，这一数字保持不变。多数 最近，金黄色念珠菌在全球范围内成为一种具有多重耐药性的机会性真菌，包括 美国，很容易在住院患者和疗养院居民之间传播 导致医疗保健领域的重大疫情。根据美国疾病控制和预防中心的数据 预防(CDC)，美国90%的金黄色葡萄球菌菌株对氟康唑耐药，30% 对两性霉素B耐药，5%对棘球菌素耐药。因此，一些菌株 金黄色葡萄球菌对所有三大类临床使用的抗真菌药物都表现出泛耐药 尤其令人担忧的是。事实上，在最近发布的美国抗生素耐药性威胁报告中， 美国疾病控制与预防中心已将C.Auris列为仅有的5个需要迅速采取积极行动的“紧急威胁”之一，因为 人们严重担心多重和泛耐药的金黄色葡萄球菌分离物将传播并流行，以及 在接下来的几年里，大多数是无法治愈的。因此，迫切需要开发新的疗法。 对抗这种新出现的病原体。为了克服这一巨大的挑战，我们提出了一种高效的方法 通过在学术界(我们的实验室)和一个非营利性组织之间建立新型的合作伙伴关系 (疟疾药物风险投资，MMV)，以执行MMV的高通量筛选(HTS) 包含18万个小分子化合物的化学文库，用于鉴定新的高价值化合物 对金黄色葡萄球菌的抗真菌活性。尽管类似的方法在寄生虫学中产生了重大影响 菲尔德，这些MMV的文库以前从未被筛选过抗真菌活性。为此，我们提出了 I)对MMV的化学文库进行HTS，以鉴定具有新结构的高价值化合物 对金黄色葡萄球菌的抗真菌活性，我们最近将使用384孔微滴定板模型 我们实验室为筛选MMV的“热门一代”(140K化合物)和“多样性”(40K化合物)而开发的 化合物)化学文库，以确定金黄色葡萄球菌生长的抑制物；以及ii)表征 通过进行一系列体外测试来进一步确定它们的抗真菌活性和 安全/毒性特性。

Candida species represent the most frequent etiological agents of opportunistic fungal invasive infections in an expanding spectrum of immune- and medically-compromised patients, and candidiasis now represents the third-to-fourth most frequent nosocomial infection worldwide, carrying unacceptably high mortality rates of 30-60%, which alarmingly have remained unchanged during the last three decades. Most recently, Candida auris has emerged as a multi-drug resistant opportunistic fungus around the globe, including the U.S, with a notable ability to easily spread between hospitalized patients and nursing home residents leading to major outbreaks in healthcare settings. According to data from the Centers for Disease Control and Prevention (CDC), 90% of C. auris strains in the U.S. have been resistant to fluconazole, 30% have been resistant to amphotericin B, and 5% have been resistant to echinocandins. Thus, the fact that some strains of C. auris demonstrate pan-resistance to all three major classes of clinically-used antifungals agents is particularly concerning. Indeed, in its recently released Antibiotic Resistance Threats in the United States, the CDC has designated C. auris as one of only 5 “Urgent Threats” requiring swift and aggressive action, since there is a grave concern that multi- and pan-resistant C. auris isolates will spread and become prevalent, and mostly untreatable, in the years to come. Thus, there is dire need for the development of novel therapeutics against this emerging pathogen. To conquer this formidable challenge, we propose a highly efficient approach by establishing a novel partnership between academia (our laboratory) and a non-for profit organization (Medicines for Malaria Ventures, MMV) in order to perform high throughput screening (HTS) of MMV’s chemical libraries containing 180,000 small molecule compounds to identify high value compounds with novel antifungal activity against C. auris. Although similar approaches have had a major impact in the Parasitology field, these MMV’s libraries have never before been screened for antifungal activity. To this end, we proposed the following: i) perform HTS of MMV’s chemical libraries to identify high value compounds with novel antifungal activity against C. auris, for which we will use a 384-well microtiter plate based model recently developed in our laboratory to screen MMV’s “Hit-Generation” (140K compounds) and “Diversity” (40K compounds) chemical libraries in order to identify inhibitors of C. auris growth; and ii) to characterize the leading compounds by performing a battery of in vitro tests to further establish their antifungal activity and safety/toxicity properties.